Bi-directional Force Communication on Cell-Matrix

Project Information

BiFCCM

Grant agreement ID: 840290

DOI

10.3030/840290

Project closed

EC signature date 10 April 2019

Start date 1 October 2019

End date 13 October 2021

Funded under

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Total cost

€ 178 320,00

EU contribution

€ 178 320,00

Coordinated by

KATHOLIEKE UNIVERSITEIT LEUVEN
Belgium

Periodic Reporting for period 1 - BiFCCM (Bi-directional Force Communication on Cell-Matrix)

Reporting period: 2019-10-01 to 2021-09-30

Summary of the context and overall objectives of the project

In tissue, cells are living in a 3D environment. Like planets in space, cells are not floating around and freely moving. Their movement and general behavior are governed by a variety of physical interactions. At the cellular level, these interactions comprise of molecular forces mediated by the mechanical reciprocity between the cell and the surrounding environment. These phenomena play a key role in cell migration and development, tissue regeneration and homeostasis, and pathologic changes. Mechanical reciprocity between cells and their surroundings is mostly observed in natural extracellular matrix (ECM), like collagen and fibrin gels. Natural ECMs possess a fibrous structure and complex nonlinear mechanics, including the strain–stiffening behavior, time-dependent viscoelasticity, and mechanical plasticity. However, the lower tunability of their bio/mechanical properties hinders the systematic study of the role of nonlinear mechanics in cell-matrix physical interactions. Moreover, the high degradability of natural ECMs does not allow the discrimination between physical interactions and enzyme-related biochemically remodeling. A comprehensive understanding of the interactions at the cell-matrix interface would enable the rational design of the next generation of biomaterials, with the goal of matching tissue and ECM properties for the development of improved in vitro models, and wide applications in regenerative medicine and tissue engineering. In the project, we combed a fibrous synthetic material with unique mechanical properties and advanced fluorescence microscopy techniques to investigate how cellular forces are related to the mechanical properties of the matrix, and how these affect cellular behavior.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

Here, we recreate for the first time the bi-directional cell-matrix physical interactions observed in biological hydrogels using synthetic hydrogels formed from polyisocyanide polymers (PIC). Our results show that PIC gels respond to cellular tractions in a manner similar to natural ECMs. Cells are able to physically induce fibre alignment and densification in the pericellular region, creating tunnels to migrate through the PIC matrix. Cellular traction forces can generate extensive fibre displacements and present a long-range stress propagation through the fibrous network. These physical interactions eventually increase the bulk storage moduli of cell-containing gels, as shown by a combination of three–dimensional traction force microscopy (3D TFM) and live-cell rheological tests. Together with the analysis of matrix remodelling, we elucidated that matrix stiffening arises from the cell-induced strain-stiffening and the rearrangement of fiber network by plastic remodelling. Both these phenomena are caused by cellular traction forces, but occur at different time scales. To further demonstrate the potential of this material to decipher the complex cell-matrix physical interactions, we investigated how changes in the mechanical or biochemical properties of PIC matrices were related to cell morphology, matrix remodeling and deformation, and force propagation. Notably, PIC gels showed cell-induced mechanical dynamics comparable with those observed in collagen and Matrigel matrices, while possessing a custom design manner. Our work showcases the flexible applications of synthetic fibrous networks in providing insights into cell-matrix interactions and paving the way for the rational design of improved biomaterials for the understanding of matrix biology.
In terms of the outreach activities, as a committee member, we organized a ‘SUMMER SCHOOL: FEEL THE FORCE’ together with the group of Prof. Dr. Hans van Oosterwyck (KU Leuven) on 15-17th Sept. 2021 (https://www.kuleuven.be/english/summer-schools/feeltheforce/home). I presented my results acquired during this fellowship in a talk (Title: Synthetic fibrous hydrogels as a platform to decipher cell-matrix physical interactions). The summer school attracted more than 30 ‘force lovers’ from many different labs within Europe (Belgium, the Netherlands, France, and Germany).
Apart from this, the results were also disseminated in conferences, namely MechanoChemBio2021, CHAINS, EACR-AACR-ASPIC Conference on Tumor Microenvironment, and in intra-department symposiums that involved both poster and oral presentation. Unfortunately, the COVID-imposed restrictions did not allow participation in other events.
We are currently finishing two article publications related to this project, one is submitted, and a second one is under preparation.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

As a new class of smart polymers for 3D cell culture, polyisocyanides (PIC) shows numerous attractive properties, such as the biomimetic nonlinear mechanics, the flexibility for custom bio-functionalization, and the ease of handling in cell culture experiments. The results acquired during this project demonstrate that PIC gels respond to cellular forces in a manner similar to natural collagen and Matrigel matrices, albeit being fully tuneable. The combination with the methods established, e.g. matrix remodeling analysis and beads-free TFM approach, shed light on the great potential of PIC gels in mechanobiology studies and tissue engineering applications, as an artificial material. These results and methods will broaden the market of PIC gels and boost its commercialization process.

PIC gel make cells feel at home: mechanically cross talk

Schematic illustration of exploring cellular forces using fluorescene microscopy